The natural history of human breast cancer is characterized by the progressive selection and outgrowth of cells that possess increasingly aggressive properties. Among these properties, the ability to metastasize is the most important determinant of clinical outcome since metastatic breast cancer is, at present, an incurable disease. For most types of human cancer, residual tumor cells remain following treatment that are not detected by conventional clinical testing. In the case of breast cancer, disseminated tumor cells are typically present at the time of diagnosis and have the ability to survive in a dormant state within tissues for extended periods of time, either as solitary cells or as micrometastases, and then emerge from dormancy and resume growth at a later date. As such, metastasis, tumor dormancy, and recurrence constitute fundamental clinical manifestations of tumor progression that collectively are responsible for the vast majority of breast cancer deaths. Nevertheless, while these aspects of tumor progression are of unrivaled clinical importance, the mechanisms underlying them are largely unknown. Accordingly, the principal goal of this Mouse Models of Human Cancer Consortium (MMHCC) application is to develop new conceptual and technical approaches to understanding the mechanisms responsible for breast cancer metastasis, dormancy, and recurrence. To accomplish this, state-of-the-art molecular, genetic, genomic, cellular, and intravital imaging methods will be used to interrogate a series of well-validated genetically engineered mouse models for breast cancer progression developed by the investigators of this program. This application represents a highly integrated, multidisciplinary effort to understand critical aspects of tumor progression and breast cancer biology by senior investigators from the University of Pennsylvania, the Albert Einstein College of Medicine, McGill University, and the University of California, Davis. By elucidating the biology of breast cancer progression, this MMHCC program can accelerate the development of more effective approaches to detecting, arresting, and eradicating disseminated tumor cells.